Available structures
PDBOrtholog search: PDBe RCSB
AliasesCRH, CRF, CRH1, corticotropin releasing hormone
External IDsOMIM: 122560; MGI: 88496; HomoloGene: 599; GeneCards: CRH; OMA:CRH - orthologs
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 8: 66.18 – 66.18 MbChr 3: 19.75 – 19.75 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that belongs to corticotropin-releasing factor family. In humans, it is encoded by the CRH gene.[5] Its main function is the stimulation of the pituitary synthesis of adrenocorticotropic hormone (ACTH), as part of the hypothalamic–pituitary–adrenal axis (HPA axis).

Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide derived from a 196-amino acid preprohormone. CRH is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress. Increased CRH production has been observed to be associated with Alzheimer's disease and major depression,[6] and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia.[5]

In addition to being produced in the hypothalamus, CRH is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta, CRH is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of CRH occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, CRH may act as a trigger for parturition.[5]

A recombinant version for diagnostics is called corticorelin (INN).

Actions and psychopharmacology

CRH is produced in response to stress, predominantly by parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and is released at the median eminence from neurosecretory terminals of these neurons into the primary capillary plexus of the hypothalamo-hypophyseal portal system. The portal system carries the CRH to the anterior lobe of the pituitary, where it stimulates corticotropes to secrete adrenocorticotropic hormone (ACTH) and other biologically-active substances (β-endorphin). ACTH stimulates the synthesis of cortisol, glucocorticoids, mineralocorticoids and DHEA.[7]

In the short term, CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention.[8]

During chronic stress conditions such as post-traumatic stress disorder (PTSD), blood serum levels of CRH are decreased in combat veterans with PTSD compared to healthy individuals.[9] It is believed that chronic stress enhances the negative feedback inhibition of the HPA axis, resulting in lower CRH levels and HPA function.[10][11][12]

Abnormally high levels of CRH have been found in people with major depression,[13][6] and in the cerebrospinal fluid of people who have committed suicide.[14]

Corticotropin-releasing hormone has been shown to interact with its receptors, corticotropin-releasing hormone receptor 1 (CRFR1) and corticotropin-releasing hormone receptor 2 (CRFR2), in order to induce its effects.[15][16][17][18] Injection of CRH into the rodent paraventricular nucleus of the hypothalamus (PVN) can increase CRFR1 expression, with increased expression leading to depression-like behaviors.[19] Sex differences have also been observed with respect to both CRH and the receptors that it interacts with. CRFR1 has been shown to exist at higher levels in the female nucleus accumbens, olfactory tubercle, and rostral anteroventral periventricular nucleus (AVPV) when compared to males, while male voles show increased levels of CRFR2 in the bed nucleus of the stria terminalis compared to females.[20]

The CRH-1 receptor antagonist pexacerfont is currently under investigation for the treatment of generalized anxiety disorder.[21] Another CRH-1 antagonist antalarmin has been researched[citation needed] in animal studies for the treatment of anxiety, depression and other conditions, but no human trials with this compound have been carried out.

The activation of the CRH1 receptor has been linked with the euphoric feelings that accompany alcohol consumption. A CRH1 receptor antagonist developed by Pfizer, CP-154,526 is under investigation for the potential treatment of alcoholism.[22][23]

Increased CRH production has been observed to be associated with Alzheimer's disease.[6]

Although one action of CRH is immunosuppression via the action of cortisol, CRH itself can actually heighten the immune system's inflammation response, a process being investigated in multiple sclerosis research.[24]

Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia.[5]

Alpha-helical CRH-(9–41) acts as a CRH antagonist.[25]

Role in parturition

CRH is synthesized by the placenta and seems to determine the duration of pregnancy.[26]

Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition:[27]

In culture, trophoblast CRH is inhibited by progesterone, which remains high throughout pregnancy. Its release is stimulated by glucocorticoids and catecholamines, which increase prior to parturition lifting this progesterone block.[28]


The 41-amino acid sequence of CRH was first discovered in sheep by Vale et al. in 1981.[29] Its full sequence is:

The rat and human peptides are identical and differ from the ovine sequence only by 7 amino acids.[30]

Role in non-mammalian vertebrates

In mammals, studies suggest that CRH has no significant thyrotropic effect. However, in representatives of all non-mammalian vertebrates, it has been found that, in addition to its corticotropic function, CRH has a potent thyrotropic function, acting with TRH to control the hypothalamic–pituitary–thyroid axis (TRH has been found to be less potent than CRH in some species).[31][32]

See also


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000147571Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000049796Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d "Entrez Gene: CRH corticotropin releasing hormone".
  6. ^ a b c Raadsheer FC, van Heerikhuize JJ, Lucassen PJ, Hoogendijk WJ, Tilders FJ, Swaab DF (September 1995). "Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression". The American Journal of Psychiatry. 152 (9): 1372–1376. doi:10.1176/ajp.152.9.1372. PMID 7653697.
  7. ^ "Corticotrophin-releasing hormone". 5 September 2012. Society for Endocrinology. Archived from the original on 20 October 2016. Retrieved 9 July 2013.
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  9. ^ Ramos-Cejudo J, Genfi A, Abu-Amara D, Debure L, Qian M, Laska E, et al. (2021). "CRF serum levels differentiate PTSD from healthy controls and TBI in military veterans". Psychiatric Research and Clinical Practice. 3 (4): 153–162. doi:10.1176/appi.prcp.20210017. PMC 8764614. PMID 35211666.
  10. ^ Yehuda R, Hoge CW, McFarlane AC, Vermetten E, Lanius RA, Nievergelt CM, et al. (October 2015). "Post-traumatic stress disorder". Nature Reviews. Disease Primers. 1: 15057. doi:10.1038/nrdp.2015.57. PMID 27189040. S2CID 1510508.
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  16. ^ Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, et al. (October 1997). "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin". Neuropharmacology. 36 (10): 1439–1446. doi:10.1016/S0028-3908(97)00098-1. PMID 9423932. S2CID 6235036.
  17. ^ Ramot A, Jiang Z, Tian JB, Nahum T, Kuperman Y, Justice N, et al. (March 2017). "Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress". Nature Neuroscience. 20 (3): 385–388. doi:10.1038/nn.4491. PMID 28135239. S2CID 5017743.
  18. ^ Bale TL, Vale WW (10 February 2004). "CRF and CRF Receptors: Role in Stress Responsivity and Other Behaviors". Annual Review of Pharmacology and Toxicology. 44 (1): 525–557. doi:10.1146/annurev.pharmtox.44.101802.121410. ISSN 0362-1642. PMID 14744257.
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  21. ^ "Study of Pexacerfont (BMS-562086) in the Treatment of Outpatients With Generalized Anxiety Disorder". 1 August 2008. Retrieved 3 August 2008.
  22. ^ "Drug Has Potential To Prevent Alcoholics From Relapsing". Science News. ScienceDaily. 2 August 2008. Retrieved 9 August 2008.
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  29. ^ Vale W, Spiess J, Rivier C, Rivier J (September 1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin". Science. 213 (4514): 1394–1397. Bibcode:1981Sci...213.1394V. doi:10.1126/science.6267699. PMID 6267699.
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  31. ^ Seasholtz AF, Valverde RA, Denver RJ (October 2002). "Corticotropin-releasing hormone-binding protein: biochemistry and function from fishes to mammals". The Journal of Endocrinology. 175 (1): 89–97. doi:10.1677/joe.0.1750089. PMID 12379493.
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Further reading